Dear editorial board , we highly appreciate the thoughtful comments by Orsi et al. and Rafat et al. on our recent report on the impact of short-term complement inhibition in patients with thrombotic microangiopathy (TMA) associated with postpartum hemorrhage (PPH). We emphasize the point that the precipitating causes of TMA and disseminated intravascular coagulation (DIC) in the complex context of pregnancy-associated physiological changes and acute obstetric complications, particularly bleeding and mass transfusions, cannot safely be discriminated and often leave the treating physician at a loss. A pragmatic therapeutic approach is needed which incorporates early and temporary complement inhibition in selected cases. How can we recognize the interplay between hypercoagulation and hyperfibrinolysis, particularly in the event of major bleeding and how should we distinguish from TMA as rightfully pointed out by Orsi et al.? Patients with bleeding after major surgery or those with obstetric complications are particularly susceptible to "the massive bleeding or consumptive type of disseminated intravascular coagulation (DIC)"1Wada Hideo et al.Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines.Journal of intensive care. 20 Feb. 2014; 2https://doi.org/10.1186/2052-0492-2-15Crossref Scopus (228) Google Scholar. Here, the balance between coagulation and fibrinolysis is disrupted, resulting in the consumption of clotting factors and bleeding. However, standard procedures for quantifying C3 or C5 activation in relation to coagulation factors, particularly in the context of substitution of fresh frozen plasma and red blood cells, are currently lacking. Moreover, complement regulation occurs on cell surfaces as well as in the fluid phase, making measurements in blood samples less informative and pathophysiologic considerations more complex. For pregnancy, the need for adapted scoring systems for DIC has long been suggested2Erez Offer et al.DIC in Pregnancy - Pathophysiology, Clinical Characteristics, Diagnostic Scores, and Treatments.Journal of blood medicine. 2022; 13: 21-44https://doi.org/10.2147/JBM.S273047Crossref Scopus (34) Google Scholar. In a recent study, the nonpregnant ISTH nonovert DIC score, originated by the International Society on Thrombosis and Hemostasis (ISTH), was unable to identify any of the patients with nonovert DIC in a pregnancy cohort because of the chosen cut-off values for fibrinogen and d-dimers3Alhousseini Ali et al.Nonovert disseminated intravascular coagulation (DIC) in pregnancy: a new scoring system for the identification of patients at risk for obstetrical hemorrhage requiring blood product transfusion.The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2022; 35: 242-257https://doi.org/10.1080/14767058.2020.1716330Crossref Scopus (9) Google Scholar. In contrast, a newly developed pregnancy-specific nonovert DIC scoring system demonstrated improved sensitivity and specificity in identifying patients at risk for obstetrical hemorrhage requiring blood product transfusion compared to existing scoring systems3Alhousseini Ali et al.Nonovert disseminated intravascular coagulation (DIC) in pregnancy: a new scoring system for the identification of patients at risk for obstetrical hemorrhage requiring blood product transfusion.The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2022; 35: 242-257https://doi.org/10.1080/14767058.2020.1716330Crossref Scopus (9) Google Scholar. While the patients in our study could have been sorted into a high-risk or low-risk group prior to delivery, neither test would discriminate between DIC and TMA. Rafat et al. raise doubts regarding the need for complement inhibition in clinical TMA in the absence of a confirmed genetic predisposition. The authors suggest that expedited genetic testing may help identify patients who could benefit from complement inhibition and contend that postpartum TMA generally has a favorable prognosis with supportive care only. At our hands and within the German health-care system, "fast track genetic testing" with turn-around times of less than 3-4 weeks is not available (and will not be in the near future). This time frame has also been reported in the cited case-studies in the commentary4Doreille Alice et al.How I treat thrombotic microangiopathy in the era of rapid genomics.Blood. 2023; 141: 147-155https://doi.org/10.1182/blood.2022015583Crossref Scopus (3) Google Scholar. Currently there is not enough evidence to prove the concept that the presence of aHUS risk-haplotypes in the absence of proven aHUS susceptibility variants (pathogenic variants) can be interpreted as a genetic modifier exacerbating the triggering event of PPH. In real-world scenarios the discrimination between postpartum acute kidney injury (AKI, e.g. after HELLP) versus postpartum TMA causing AKI (as in aHUS) is often done in retrospect, when the clinical course and diagnostics have unfolded. Data from well-characterized aHUS cohorts in pregnant patients suggest that an identifiable genetic abnormality may be present in as much as 40-55 % of all cases with about 30-70% of all patients reaching end-stage kidney failure at 8 years after delivery5Bruel Alexandra et al.Hemolytic Uremic Syndrome in Pregnancy and Postpartum.Clinical journal of the American Society of Nephrology : CJASN. 2017; 12: 1237-1247https://doi.org/10.2215/CJN.00280117Crossref PubMed Scopus (156) Google Scholar, 6Fakhouri Fadi et al.Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.Journal of the American Society of Nephrology : JASN. 2010; 21: 859-867https://doi.org/10.1681/ASN.2009070706Crossref PubMed Scopus (344) Google Scholar, 7Huerta Ana et al.A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome.Kidney international. 2018; 93: 450-459https://doi.org/10.1016/j.kint.2017.06.022Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar. The decision to treat with complement inhibition should therefore not be postponed, since neither genetic testing nor biopsy confirmation is needed for treatment initiation as opposed to treatment duration. We advocate for only short-term complement inhibition, which we deem advantageous when initiated promptly, ideally within the initial 72 hours. With the currently available tools and knowledge, it remains impossible to discern all contributing factors in patients with pregnancy-related TMA. This gap in knowledge underscores the importance of continued research to develop robust diagnostic tools and therapeutic strategies tailored to the unique pathophysiological mechanisms underlying TMA and/or DIC in different clinical scenarios, thus, improving outcomes in this critical area of maternal health. The Interaction Between Coagulation and Complement Cascades in the Management of Thrombotic Microangiopathies Related to Postpartum HemorrhageKidney International ReportsPreviewWe read with great interest the report by Kaufeld et al.1 who studied the impact of short-term complement inhibition in patients with thrombotic microangiopathy associated with postpartum hemorrhage.1 We agree with the authors regarding the need to propose a pragmatic management model by presenting a real-world cohort of patients affected by this infrequent complication. Nonetheless, we believe that some aspects deserve further discussion.
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